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Diagnostic criteria
Criteria for Neurofibromatosis Type 1 (NF1)
A diagnosis of NF1 is usually made clinically through medical examination of the body as this is considered most reliable. However, more and more frequently diagnosis is made through a blood test in which the NF1 gene is analysed for changes.
To receive a clinical diagnosis of NF1, an individual must have at least two of the following diagnostic criteria:
- A parent with NF1 based on diagnostic criteria.
- 6 or more Café-au-lait marks (CALs) which are 5 mm or larger in pre-pubertal children, or 15 mm or larger for anyone who has passed through puberty.
- Freckling under the arms (axillary) or in the groin area (inguinal)
- Presence of two or more neurofibromas of any type or one or more plexiform neurofibromas.
- Two or more iris Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities (CAs)—defined as bright, patchy nodules imaged by optical coherence tomography (OCT)/near-infrared reflectance (NIR) imaging.
- A distinctive osseous lesion such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone.
- Optic Pathway Glioma (OPG).
Diagnostic updates for NF2-SWN and SWN
In 2022, the diagnostic criteria for neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) was updated, to include the latest in NF research and clinical findings, and to improve diagnostic accuracy and appropriate medical care.
The former diagnostic criteria for NF2 and schwannomatosis classified patients primarily based on clinical features; however, it is now apparent that the manifestations of these diseases span the same continuum. For this reason, "schwannomatosis" no longer defines a distinct syndrome, but is now used as an umbrella term to describe the overlapping conditions in which a patient has many schwannomas. The term NF2 has now been retired.
Criteria for NF2-related schwannomatosis (formerly NF2)
A diagnosis of NF2-related schwannomatosis can be made when a patient has one of the following:
Bilateral vestibular schwannomas (VS)
An identical NF2 pathogenic variant* in at least two anatomically distinct NF2-related tumors (schwannoma, meningioma, and/or ependymoma)
Either two Major OR one Major and two Minor criteria are present as follows:
MAJOR CRITERIA
- Unilateral vestibular schwannoma
- First-degree relative other than a sibling with NF2-related schwannomatosis
- Two or more meningiomas. (Note: single meningioma qualifies as a minor criterion)
- NF2 pathogenic variant* in an unaffected tissue such as blood
*When the variant is present at significantly less than 50%, the diagnosis is mosaic NF2-related schwannomatosis
MINOR CRITERIA
Can count more than one of a type (e.g., two schwannomas = two minor criteria)
- Ependymoma; schwannoma (Note: if the major criterion is unilateral VS, at least one schwannoma must be dermal in location)
Can count only once
- Juvenile subcapsular or cortical cataract; retinal hamartoma; epiretinal membrane in a person aged less than 40 years; meningioma
(Note: multiple meningiomas qualify as a major criterion; meningioma cannot be used as both a major and a minor criteria)
Criteria for all types of Schwannomatosis
Mosaicism is confirmed for LZTR1-related, SMARCB1-related, or NF2-related schwannomatosis by either of the following:
- Clearly less than 50% pathogenic variant allele fraction (VAF) in blood or saliva
OR
- Pathogenic variant not detected in blood or saliva but shared pathogenic variant in two or more anatomically unrelated tumors
Previously classified as “schwannomatosis with SMARCB1 mutation”.
A diagnosis of SMARCB1-related schwannomatosis can be made when a patient meets one of the following criteria:
- At least one pathologically confirmed schwannoma or hybrid nerve sheath tumor AND a SMARCB1 pathogenic variant in an unaffected tissue such as blood or saliva
- A common SMARCB1 pathogenic variant in two anatomically distinct schwannomas or hybrid nerve sheath tumors
Note: diagnosis requires surgical specimen to confirm tumor histology
Previously classified as “schwannomatosis with LZTR1 mutation”.
A diagnosis of LZTR1-related schwannomatosis can be made when a patient meets one of the following criteria:
- At least one pathologically confirmed schwannoma or hybrid nerve sheath tumor AND an LZTR1 pathogenic variant in an unaffected tissue such as blood or saliva
- A common LZTR1 pathogenic variant in two anatomically distinct schwannomas or hybrid nerve sheath tumors
Note: diagnosis requires surgical specimen to confirm tumor histology
Previously classified as “schwannomatosis without identified mutation in blood"
A diagnosis of 22q-related schwannomatosis can be made when an individual does not meet criteria for NF2-related schwannomatosis, SMARCB1-related schwannomatosis, or LTZR1-related schwannomatosis, and has both of the following molecular features:
- Loss of heterozygosity (LOH) of the same chromosome 22q markers in two anatomically distinct schwannomas or hybrid nerve sheath tumors
AND
- A different NF2 pathogenic variant in each tumor which cannot be detected in unaffected tissue
Note: diagnosis requires at least two surgical specimens
A diagnosis of schwannomatosis-NOS (not otherwise specified) can be made if both of the following criteria are met and genetic testing was not performed or is not available:
- presence of two or more lesions on appropriate imaging consistent with non-intradermal schwannomas, and
- pathologic confirmation of at least one schwannoma or hybrid nerve sheath tumor
A diagnosis of schwannomatosis-NEC (not elsewhere classified) can be made if both of the above criteria are met and genetic testing does not reveal a pathogenic variant in known schwannomatosis related genes.
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